Adjustable rate drug delivery implantable device

ABSTRACT

Embodiments herein relate to an implantable device comprising a casing, a semi-permeable membrane plug at or near a first end of the casing, a piston, beads, and an opening for release of the beads from the implantable device within a body of a human or an animal; wherein the implantable device is configured to be implanted within the body of the human or the animal during delivery of the beads into the body of the human or the animal; wherein the beads comprise a core and a shell with the core being enclosed by the shell and the beads contain a drug; and wherein the implantable device is configured to produce a desired flow rate of elution of the drug from the implantable device when the implantable device is implanted within the body of the human or the animal.

CROSS REFERENCE OF RELATED APPLICATIONS

The present application is continuation of U.S. patent application Ser.No. 16/525,477, filed on Jul. 29, 2019, which is a continuation of U.S.patent application Ser. No. 15/661,575, filed on Jul. 27, 2017 (Now U.S.patent Ser. No. 10/406,336B2, issued on Sep. 10, 2019), which claimsbenefit of priority to U.S. Provisional Application 62/370,675,entitled, “Controlled Drug Delivery Implant,” filed on Aug. 3, 2016,which is incorporated herein by reference in its entirety. The presentinvention is related U.S. Patent Publications: (1) US 20140056962entitled “DRUG DELIVERY SYSTEM;” (2) US 20130115265 entitled “DRUGDELIVERY SYSTEM;” (3) US 20130078286 entitled “DRUG DELIVERY SYSTEM;”(4) US 20120058171 entitled “ZOO-TECHNICAL IMPLANT;” (5) US 20120052108entitled “MACROCYCLIC LACTONE DRUG DELIVERY SYSTEM;” (6) US 20100203104entitled “DELIVERY SYSTEM FOR RISPERIDONE;” (7) US 20100129425 entitled“VAGINAL DELIVERY SYSTEM FOR MIRTAZAPINE;” (8) US 20100104619 entitled“DELIVERY SYSTEM FOR A NON-STEROIDAL NON-IONIZED HYDROPHILIC DRUG;” (9)US 20090081278 entitled “Drug Delivery System;” (10) US 20080112892entitled “X-Ray Visible Implant;” (11) US 20070141102 entitled “Drugdelivery system based on polyethylene vinylacetate copolymers;” (12) US20060280771 entitled “Drug delivery system;” (13) US 20130280334entitled “Nanostructured Gels Capable of Controlled Release ofEncapsulated Agents;” (14) US 20100129459 entitled “Biodegradablemicrosphere composition suitable for the controlled release of glucosecontrolling peptide and formulation thereof,” (15) U.S. application Ser.No. 15/011,181, entitled “FULLY OR PARTIALLY DEVICE FOR CONTROLLED DRUGDELIVERY.” All U.S. Patents and U.S. Patent Publications referred aboveand in the application are incorporated, in relevant parts for thepurposes of written description, herein by reference in their entirety.

FIELD OF THE INVENTION

The present invention is directed to an adjustable rate drug deliveryimplant device wherein the flow rate of elution (i.e., release) of thedrug from the device can be maintained substantially constant, increasedor decreased with time, or even stopped momentarily.

BACKGROUND OF THE INVENTION

Though thousands of effective biopharmaceuticals exist for a wide arrayof medical/clinical indications, adherence to drug administrationremains a severe problem in fully treating these diseases. Given thedifficulties in taking a medication every day, or numerous timesthroughout the day, and the complexities in properly delivering a druginto the body, a small implantable device would be a convenient solutionfor a large number of patient populations. Such an implantable devicewould safely allow for the controlled release of a substance into thebody, and this drug delivery platform could be used universally for avariety of conditions.

An important limitation in many existing drug delivery implants is thattheir drug release profiles are not well-controlled. Though it may berequired in certain cases, most drug release profiles in an implantabledevice are undesirable as the drug concentration decreases as a functionof time as the drug runs out. The present invention overcomes theselimitations and furthermore provides many other added benefits such astargeted delivery of the drug to a target (e.g., tissue or organ) in thebody.

SUMMARY OF THE INVENTION

An embodiment relates to an implantable device comprising a pumpcomprising a casing, a semi-permeable membrane plug at or near a firstend of the casing, a piston, beads, and an opening for release of thebeads from the implantable device within a body of a human or an animal;wherein the implantable device is configured to be implanted within thebody of the human or the animal during delivery of the beads into thebody of the human or the animal; wherein the beads comprise a core and ashell with the core being enclosed by the shell and the beads contain adrug; and wherein the pump is configured to produce a desired flow rateof elution of the drug from the implantable device when the implantabledevice is implanted within the body of the human or the animal.

Preferably, the drug and/or the beads comprise a targeting material ortargeting molecule that binds to a certain organ, tissue, object or aspecific site within the body of the human or the animal.

Preferably, the shell comprises a stimuli-responsive polymer, morepreferably a stimuli-responsive biodegradable polymer, configured tobreak the shell, before or after implanting or attaching the implantabledevice in or on a body of a human or an animal, when the beads areexposed to an external stimulus.

Preferably, the shell comprises a first material and a second material;wherein the first material comprises a metal-containing material or afirst biodegradable material; wherein the second material comprises asecond biodegradable material; wherein the first material is distributedin the second material; wherein the first material is configured tocreate pores in the second material; wherein the pores allow the drug toflow from within the beads to outside the beads.

Preferably, the metal-containing material is configured to form pores inthe shell, before or after implanting or attaching the implantabledevice in or on a body of a human or an animal, when the beads areexposed to an external stimulus.

Preferably, the metal-containing material comprises metallic particles.

Preferably, the metallic particles comprise iron-containing ormanganese-containing particles, or an iron-containing ormanganese-containing polymer.

Preferably, the first and second materials comprise polymers.

Preferably, the first material comprises poly lactic acid (PLA) or aniron-containing polymer and the second biodegradable material comprisespoly ε-caprolactone (PCL).

Preferably, the core comprises the drug and a polymer. Preferably, thecore comprises an emulsion of the drug and the polymer.

Preferably, the desired flow rate of elution of the drug issubstantially constant.

Preferably, the desired flow rate of elution of the drug issubstantially constant for a first period of time and substantially zerofor a second period of time, or vice-versa, or any combinations thereof.

Preferably, the desired flow rate of elution of the drug is increasingor decreasing with time, or any combinations thereof.

The implantable device could further comprise a sensor configured tomonitor the concentration of the drug in the body of the human or theanimal.

The implantable device could further comprise a side wall at or near asecond end of the casing, wherein the casing is substantially tubularhaving at least the first end of the casing and the second end of thecasing, and the second end of the casing is opposite the first end ofthe casing.

The implantable device could further comprise a sonicator or a platewith holes therein, wherein the sonicator or the plate is locatedbetween the piston and the side wall.

The implantable device could further comprise a first chamber betweenthe semi-permeable plug and the piston, a second chamber between thepiston and the sonicator or the plate, and a third chamber between thesecond chamber and the side wall, wherein the first chamber comprises asalt solution, the second chamber comprises the beads, and the thirdchamber comprises a foam.

Preferably, the sonicator is configured to sonicate and increaseporosity of the foam.

Preferably, some or all of the holes in the plate are filled with aphase-change material.

Preferably, the side wall contains the sensor.

Another embodiment relates to an implantable device comprising a pumpthat is configured to produce a flow rate of elution of a drug from theimplantable device to be maintained substantially constant, increased ordecreased with time, or even stopped momentarily; beads comprising acore and a shell, the core being enclosed by the shell, the corecomprising the drug, and the shell comprising a first material and asecond material; wherein the first material is distributed in the secondmaterial; wherein the first material is configured to create pores inthe shell; wherein the pores allow the drug to be released from the coreto the exterior of the shell through the pores.

Preferably, the first material comprises a metal-containing materialthat forms the pores in the shell or a first biodegradable material thatdegrades over time, and the second material comprises a secondbiodegradable material.

Preferably, the metal-containing material is configured to form pores inthe shell, before or after implanting or attaching the implantabledevice in or on a body of a human or an animal, when the shell isexposed to an external stimulus.

DESCRIPTION OF FIGURES

FIG. 1 shows a schematic of an implantable device according to oneembodiment disclosed herein.

FIG. 2 (prior art) is a diagram showing how DUROS' implantable deviceworks.

FIG. 3 shows a schematic of a substantially constant drug concentrationprofile with time according to one embodiment disclosed herein.

FIG. 4 shows a schematic of a plate containing holes, some or all ofwhich that are filled with phase-change material (PCM).

FIG. 5 shows a schematic of a foam plug containing the plate of FIG. 4,further showing electrodes 1 and 2 across the foam plug.

FIG. 6 (prior art) is a schematic showing how MicroCHIPS' wirelessimplantable device works.

DETAILED DESCRIPTION OF THE INVENTION

As used in the specification and claims, the singular forms “a”, “an”and “the” include plural references unless the context clearly dictatesotherwise. For example, the term “an array” may include a plurality ofarrays unless the context clearly dictates otherwise.

Present invention provides a device for controlled delivery of drugs.

“Drug” in context of the present invention may include any therapeuticactive agent and/or a biologically active agent (i.e., an activeingredient in a pharmaceutical composition that is biologically active,such as a vaccine), irrespective of the molecular weight of such agents.The terms drug, active, active agent, therapeutic agent are usedinterchangeably. The term “drug” as used herein refers to a single drugor multiple types of drugs.

In one embodiment, the present invention relates provides a device forcontrolled delivery of drugs, comprising a micro or nano beads thatcontains drug, wherein the beads are embedded in a polymer.

“Micro or nano beads” in context of the present invention have anability to release a drug in a controlled manner. The beads may bespherical or substantially spherical in shape, having its largesttransverse dimension is equivalent to the diameter of the bead.Alternatively the bead may be non-spherical, for example, ellipsoidal ortetrahedral in shape having its largest transverse dimension isequivalent to the greatest distance within the bead from one beadsurface to another e.g., the major axis length for an ellipsoidal beador the length of the longest side for a tetrahedral bead.

An embodiment relates to implantable device systems for controlleddelivery of drugs, especially for managing therapies for chronicpatients. Therapy delivery to treat chronic ailments requires multipleadministration of a single or a multiple drug cocktail over a longperiod of time. Sustained delivery is highly desirable for delivery ofbioactive agents particularly biologicals like peptides, antibodies andnucleic acid analogs. This kind of delivery would provide optimumtherapeutic efficacy with minimum side effects and thereby improvepatient compliance.

More preferably the implantable device therapeutic systems are builtfrom bio-absorbable material. These therapeutic systems deliver the drugto an in vivo patient site and can occupy that site for extended periodsof time without being harmful to the host.

In one embodiment, the present invention relates to a device forcontrolled delivery of drugs, comprising a micro or nano beads thatcontains drug, wherein the beads are embedded in a flowable mixture suchas a liquid, an emulsion or polymer that are approved by the Food andDrug Administration (FDA) for injection into a human body, e.g., abiodegradable sol-gel or biodegradable thermoplastic polymer, includinga biodegradable foam that can be squeezed out of the implant.

In one embodiment, the present invention relates to a device forcontrolled delivery of drugs, comprising a micro or nano beads thatcontains drug, wherein the device can be implanted into specific organsor underneath the skin for an effective local or systemic delivery ofdrug.

In one embodiment, the present invention relates to a device forcontrolled delivery of drugs, comprising a micro or nano beads thatcontains drug, wherein the device provide sustained drug delivery for aprolonged period of time. Preferably, the time period of ranges fromabout 1 week to about 5 years. More preferably, the time period ofranges from about 1 month to about 3 years.

The device of the present invention is advantageous over transdermalpatches. The transdermal drug delivery system has several limitationssince skin forms a very effective barrier and thus the system issuitable for the only medications that have small enough size topenetrate the skin such as molecules having molecular weight less than500. Further, molecule with sufficient aqueous and lipid solubility,having an octanol/water partition coefficient (log P) between 1 and 3 isrequired for permeate to transverse subcutaneous and underlying aqueouslayers. Patches are known to have side effects like erythema, itching,local edema and allergic reaction can be caused by the drug, theadhesive, or other excipients in the patch formulation. Also dosedumping is one of the serious implications of patch. In one embodiment,the device of the present invention overcomes these limitations oftransdermal patch.

In one aspect of this embodiment, the device is pre-loaded in a needlesupplied with s disposable applicator.

In one embodiment, the present invention relates to a device forcontrolled delivery of drugs, comprising a micro or nano beads thatcontains drug, wherein the device is suitable for delivery of smallmolecules having molecular weight less than 500 as well as largebiologics entities like peptides, antibodies and nucleic acid analogssuch as modified RNA, small interfering RNA, anti-sense DNA or fragmentsthereof.

In one embodiment, the present invention relates to a device forcontrolled delivery of drugs, comprising a micro or nano beads thatcontains drug, wherein the device is suitable for delivery of lidocaine,diclofenec, clonidine, estradiol, estradiol/norethindrone acetate,estradiol/levonorgestrel, fentanyl, methylphenidate, nicotine,norelgestromin/ethinyl estradiol, nitroglycerin, oxybutynin,scopolamine, selegiline, testosterone, rivastigmine, rotogotine.

In one embodiment, the present invention relates to a device forcontrolled delivery of drugs, comprising a micro or nano beads thatcontains drug, wherein the device is suitable for delivery of long-termsustained release of insulin or analogs thereof, GLP-1 or analogsthereof, alone or in combination of other therapies, to treat diabetesor other metabolic conditions.

In one aspect of this embodiment, the device is suitable for delivery oflong-term release of contraceptive hormones, combination of estrogen orprogestin or singular delivery of progesterone alone and serves ascontraceptive aid for women.

In one aspect of this embodiment, the device is suitable for delivery oflong-term therapeutic benefit for ocular diseases, such as age relatedmacular degeneration, dry eye and various others.

In one aspect of this embodiment, the device is suitable for delivery ofany small molecule or biologic therapy to treat urinary bladdercomplications such as incontinence, yeast infections, bladder cancer andvarious others.

In one aspect of this embodiment, the device is suitable for delivery oftherapeutic molecules to the male reproductive organs as a means totreat medical conditions such as erectile dysfunction, prematureejaculation, testicular cancer and various others pertaining to malereproductive system.

In one aspect of this embodiment the device is suitable for delivery oftherapeutic molecules to female reproductive organs, uterus and ovaries,to treat medical conditions such as endometriosis, uterine fibroids,ovarian cancer, uterine cancer, poly cystic ovarian syndrome, andvarious other diseases pertaining to female reproductive system.

In one aspect of this embodiment, the device is suitable for delivery oftherapeutic molecules to heart conditions such as heart failure,myocardial ischemia, and various other heart diseases.

In one aspect of this embodiment, the device is suitable for delivery oftherapeutic molecules into the adipose tissue to treat conditions suchas metabolic syndrome, diabetes, hypercholesterolemia,hypertriglyceridemia and various others.

In another embodiment, the present invention relates to a device forcontrolled delivery of drugs, comprising a micro or nano beads thatcontains drug, wherein a top coating can be applied on the beads todelay release of the active agent. In another embodiment, a top coatingcan be used for the delivery of a second active agent. A layeredcoating, comprising respective layers of fast- and slow-hydrolyzingpolymer, can be used to stage release of the active agent or to controlrelease of different active agents placed in the different layers.Polymer blends may also be used to control the release rate of differentactive agents or to provide a desirable balance of coatingcharacteristics (e.g., elasticity, toughness) and drug deliverycharacteristics (e.g., release profile). Polymers with differing solventsolubilities can be used to build-up different polymer layers that maybe used to deliver different active agents or to control the releaseprofile of active agents.

The amount of an active agent present depends upon the particular theactive agent employed and medical condition being treated. In oneembodiment, the active agent is present in an effective amount. Inanother embodiment, the amount of the active agent represents from about0.01% to about 60% of the coating by weight. In another embodiment, theamount of the active agent represents from about 0.01% to about 40% ofthe coating by weight. In another embodiment, the amount of the activeagent represents from about 0.1% to about 20% of the coating by weight.

Another embodiment relates to a device comprising micro or nano beadshaving a shell comprising a first material and a second material,wherein the second material comprises a biodegradable material; a corecomprising a pharmaceutically effective composition, the core beingenclosed by the shell; wherein the first material is distributed in thebiodegradable material; wherein the first material is configured tocreate holes in the shell; wherein the holes allow the pharmaceuticallyeffective composition to be released to the exterior of the shellthrough the holes. In one embodiment, the shell could be made bypolymerizing a silica-functionalized monomer to form a silica-containingbiodegradable polymer shell.

Preferably, the first material comprises a metal-containing materialthat can be heated to form the holes or a biodegradable material thatdegrades over time. Preferably, the metal-containing material ifconfigured to be heated under radiation, before or after implanting orattaching the device in or on a body of a human or an animal, to formthe holes. Preferably, the metal-containing material comprises metallicparticles. Preferably, the metallic component comprises aniron-containing material or an iron-containing polymer. Preferably, themetallic particles comprise iron-containing particles or aniron-containing polymer. Preferably, the first material comprises abiodegradable material. Preferably, the first and second materialscomprise polymers. Preferably, the first material comprises poly lactidacid (PLA) or an iron-containing polymer and the second biodegradablematerial comprises poly ε-caprolactone (PCL). Preferably, the corecomprises an emulsion or beads of the pharmaceutically effectivecomposition and a polymer.

Preferably, the pharmaceutically effective composition comprises atargeting material or targeting molecule that binds to a certain organ,object or a specific site within a body of a human or an animal.

The implantable device of the embodiments herein can be implanted intospecific organs, such as vagina, or underneath the skin for an effectivelocal or systemic delivery of the pharmaceutical agent. In oneembodiment, the present invention relates provides device for controlleddelivery of drugs, comprising a micro or nano beads that contains drug.

The beads used in the implantable device of the embodiments herein canbe made by microfluidics. Microfluidics-based technology enables precisecontrol and manipulation of fluids constrained to micron-sizedcapillaries. Advantages of microfluidics include reduced sample size andreagent consumption, short processing times, enhanced sensitivity,real-time analysis, and automation. More specifically, drop-basedmicrofluidics allows for the creation of micron-sized emulsions that canhold discrete picoliter volumes, with drop-making frequencies of greaterthan 2,000 drops per second (2 kHz).

Soft lithography techniques could be employed to fabricate microfluidicdevices for bead fabrication. For example, in one embodiment, AutoCADsoftware was used to generate a UV photomask containing micron-sizedcapillaries of desired structure and dimension. A silicon wafer wascoated with UV photoresist, on which the photomask was placed. After UVexposure, the silicon wafer was developed with propylene glycolmonomethyl ether acetate (PGMEA) to generate a positive resist with thedesired channels exposed. Polydimethylsiloxane (PDMS) was poured atopthe positive resist and incubated at 65° C. overnight. After removingthe PDMS (now a negative resist with the desired channels) from thesilicon wafer, the inlets were punched and the PDMS was bonded to glassvia plasma-activated bonding. The devices were treated with hydrophobicAquapel to prevent the wetting of channels during drop formation. Thedevice for droplet formation is disclosed in U.S. Patent Publication20120222748, entitled “DROPLET CREATION TECHNIQUES,” which isincorporated herein, in relevant parts for the purposes of writtendescription, by reference in its entirety.

Additional U.S. Patents and Publications related to droplet formationand are incorporated herein, in relevant parts for the purposes ofwritten description, by reference in their entirety are:

U.S. Pat. No. 7,776,927 B2—This is a patent broadly describes methods ofdroplet generation and describes some potential uses in drug delivery.

US20120141589 A1—This patent describes some compounds (such as CaCO3)with which the microfluidic emulsions could be made depending on thedrug encapsulated in the emulsion, droplets and beads.

US20130202657—This publication describes a microfoam for drug delivery.Such a microfoam could be incorporated as the foam or mesh in theimplantable device of the embodiments herein.

U.S. Pat. No. 6,858,220 B2—This patent discloses an implantablebiocompatible microfluidic drug delivery system using only channels, butnot microbeads containing a drug.

US20130035574, US20130035660—These publications describe the actualchip/patch rather than the microbeads. However, the publications usemicrofluidics as well as scaffolding for drug delivery.

U.S. Pat. No. 7,560,036 B2—This patent describes in detail thefabrication of the surface substrate, and uses microneedles for drugdelivery.

The drug containing beads could be made from droplets, for example,formed in accordance with the droplet creation techniques disclosed inU.S. Patent Publication US20120222748, for the implantable device of theembodiments by crosslinking biodegradable polymer of the shell of thedrug containing beads. The crosslinking density of the biodegradablepolymer of the shell could be varied such that even for the same shellthickness, the drug containing beads with low crosslinking density wouldrupture at earlier time than the drug containing beads with highcrosslinking density when the drug containing beads are exposed to bloodserum or any other bodily fluid, for example.

The drug containing beads in the embodiments herein can be sustainedrelease particles having an inner core, which could be hollow or solidor porous, containing an active pharmaceutical ingredient, an optionalintermediate coating substantially surrounding the inner core, and anouter coating substantially surrounding the optional intermediatecoating comprising a pH independent polymer such as that disclosed inU.S. Patent Publication 20080187579, entitled “Extended-release dosageform,” which is incorporated herein, in relevant parts for the purposesof written description, in its entirety. The implantable device of theembodiments herein could have two or more bead populations wherein eachof the bead populations has a different drug release profile. The methodof preparing an extended release dosage composition comprising one ormore bead populations could be that disclosed in U.S. Patent Publication20080187579, with an additional requirement that the beads are made ofbiodegradable material such as a biodegradable polymer.

In one embodiment, the present invention relates to a device forcontrolled delivery of drugs, comprising a micro or nano beads thatcontains drug, wherein the beads comprise a biocompatible, cross-linked,biodegradable material, collagen, fibronectin, elastin, hyaluronic acidor a mixture thereof.

In one embodiment the biodegradable polymer material for the bead andfoam and/or any other material of the device may include polyglycolicacid (“PGA”), polylactic acid (“PLA”), polycaprolactic acid (“PCL”),poly-p-dioxanone (“PDO”), PGA/PLA copolymers, PGA/PCL copolymers,PGA/PDO copolymers, PLA/PCL copolymers, PLA/PDO copolymers, PCL/PDOcopolymers or combinations thereof.

In another embodiment, the biodegradable polymer material may includepolycarbonate polyurethanes, polycarbonate urea-urethanes, polyetherpolyurethanes, poly(carbonate-co-ether) urea-urethanes, polysiloxanesand the like.

The implantable device could include a device such as amonitor/transmitter with ability to detect blood glucose levels, sensehormonal levels, and/or detect body temperature. The implantable devicecould include a device such as a monitor/transmitter an ability tocommunicate to the sensors/detectors in smartphone, an ability totransmit data to iCloud, and/or an ability to sense appetite sensinghormones.

Implant Device

FIG. 1 is a schematic diagram showing the implantable device based on anosmotic pump delivery system, with several features explained below. Anosmotic pump delivery is disclosed in some of the following US patentsand applications of Intarcia Therapeutics, Inc., which are incorporatedherein, in relevant parts for the purposes of written description, byreference in their entirety:

Title Application Publication Patent DEVICES, FORMULATIONS, AND METHODS12378341 20090202608 8343140 FOR DELIVERY OF MULTIPLE BENEFICIAL Feb.12, 2009 Aug. 13, 2009 Jan. 1, 2013 AGENTS TWO-PIECE, INTERNAL-CHANNELOSMOTIC 13601939 20120330282 8367095 DELIVERY SYSTEM FLOW MODULATOR Aug.31, 2012 Dec. 27, 2012 Feb. 5, 2013 SUSTAINED DELIVERY OF AN ACTIVE13645124 20130035669 8535701 AGENT USING AN IMPLANTABLE SYSTEM Oct. 4,2012 Feb. 7, 2013 Sep. 17, 2013 RAPID ESTABLISHMENT AND/OR 1364542220130030417 TERMINATION OF SUBSTANTIAL STEADY- Oct. 4, 2012 Jan. 31,2013 STATE DRUG DELIVERY OSMOTIC DELIVERY SYSTEMS AND PISTON 1293095020110166554 8801700 ASSEMBLIES FOR USE THEREIN Jan. 19, 2011 Jul. 7,2011 Aug. 12, 2014 SELF ADJUSTABLE EXIT PORT 09045944 5997527 Mar. 23,1998 Dec. 7, 1999 OSMOTIC DELIVERY SYSTEM AND METHOD 08970530 6132420FOR ENHANCING START-UP & Nov. 14, 1997 Oct. 17, 2000 PERFORMANCE OFOSMOTIC DELIVERY SYSTEMS IMPLANTER DEVICE FOR SUBCUTANEOUS 092178246190350 IMPLANTS Dec. 22, 1998 Feb. 20, 2001 OSMOTIC DELIVERY SYSTEM09121878 6287295 SEMIPERMEABLE BODY ASSEMBLY Jul. 24, 1998 Sep. 11, 2001RATE CONTROLLING MEMBRANES FOR 09213213 6375978 CONTROLLED IMPLANTS Dec.17, 1998 Apr. 23, 2002 VALVE FOR OSMOTIC DEVICES 09748099 6508808 Dec.21, 2000 Jan. 21, 2003 OSMOTIC DELIVERY SYSTEM FLOW 09122073 6524305MODULATOR APPARATUS AND METHOD Jul. 24, 1998 Feb. 25, 2003 OSMOTICDELIVERY SYSTEM HAVING 09472600 6544252 SPACE EFFICIENT PISTON Dec. 27,1999 Apr. 8, 2003 OSMOTIC DELIVERY SYSTEM HAVING 10354142 200301397326872201 SPACE EFFICIENT PISTON Jan. 30, 2003 Jul. 24, 2003 Mar. 29, 2005MINIMALLY COMPLIANT, VOLUME- 10606407 20040019345 6939556 EFFICIENTPISTON FOR OSMOTIC DRUG Jun. 25, 2003 Jan. 29, 2004 Sep. 6, 2005DELIVERY SYSTEMS OSMOTIC DELIVERY DEVICE HAVING A 10302104 200401027627014636 TWO-WAY VALVE AND A DYNAMICALLY Nov. 21, 2002 May 27, 2004 Mar.21, 2006 SELF-ADJUSTING FLOW CHANNEL SUSTAINED DELIVERY OF AN ACTIVE10645293 20040039376 7655257 AGENT USING AN IMPLANTABLE SYSTEM Aug. 20,2003 Feb. 26, 2004 Feb. 2, 2010 OSMOTIC DELIVERY SYSTEMS AND PISTON12658570 20100185184 7879028 ASSEMBLIES FOR USE THEREIN Feb. 9, 2010Jul. 22, 2010 Feb. 1, 2011

“Intarcia's platform technology is known as the DUROS® subcutaneousdelivery system. The DUROS system is comprised of a small,matchstick-sized osmotic pump that is inserted subcutaneously (justbeneath the skin) to deliver a slow and consistent flow of medication.Each device contains an appropriate volume of drug product to treat apatient for a predetermined extended duration of time. The DUROS deviceis activated when subcutaneous tissue fluid passes through the deviceinlet, expanding the osmotic engine. The osmotic engine drives thepiston at a constant rate, delivering consistent drug levels through thedevice outlet. The device can be inserted in a subcutaneous space invarious locations on the arms and abdomen during a reimbursablein-office procedure, in as little as five minutes by a physician orphysician's assistant, and ensures 100 percent patient adherence totherapy. Delivering drugs via the DUROS technology avoids unwanted peakdrug levels often associated with toxicities and sub-therapeutic troughsoften associated with suboptimal therapeutic effects. Another key aspectof the DUROS technology is the unique formulations that maintainstability of proteins and peptides at human body temperature forextended periods of time. This advance in formulations allows continuousdelivery of effective therapy with less frequent administration therebyensuring compliance and improving patient convenience. The DUROS devicewas first used as a drug delivery technology for the FDA-approvedproduct Viadur® in the delivery of leuprolide acetate.” Source:http://www.diabetesincontrol.com/wp-content/uploads/2011/09/www.diabetesincontrol.com_images_issues_2011_09_ntarcia_platform_technology.pdf.“Intarcia's clinical stage type 2 diabetes candidate, ITCA 650 involvesthe delivery of exenatide, an approved incretin mimetic using the DUROSdelivery system. The DUROS delivery system is a matchstick-sized deviceconsisting of a cylindrical titanium alloy reservoir. Once insertedunder the skin, water from the extracellular fluid enters the device atone end, by diffusing through a semipermeable membrane directly into asalt osmotic engine that expands to drive a piston at a controlled rateof travel. This forces the drug formulation to be released in a slow andconsistent fashion through the exit port, or diffusion moderator at theother end of the device.” Id.

A diagram showing how DUROS' implantable device works is shown in FIG. 2(prior art).

In the implantable device shown in FIG. 1, here are three specificchambers and therefore four barriers separating these chambers from oneanother. Let us start by describing the device from the left side, andwork our way to the right. On the left end of the device there is asemi-permeable plug, or more specifically, an osmotic membrane (I). Thismembrane would allow for fluid from the body to flow into the device.The diffusion mechanism is osmosis because in the first chamber (II),there is a highly concentrated salt solution (>1000 nM as thephysiological ionic concentration in the human body is about 150 nM)that will result in liquid being drawn into the implant. As liquid isdrawn into the chamber, its volume increases, and this pressure pushesthe piston (III), which could made of a magnetic material, between thefirst and second chambers to the right. The cylinder surrounding thepiston III is preferably made of a non-magnetic material, such as anon-magnetic metal or a non-magnetic ceramic material. The non-magneticmetal could be titanium and stainless steel to cobalt-chromium,tungsten, and tantalum, or a host of metals that are used incardiovascular, orthopedic, and many other medical device fields, solong these metals are non-magnetic.

As the piston is pushed to the right by osmotic pressure, it decreasesthe volume of the middle chamber (IV). This chamber contains the drug inbeads in a flowable mixture, which could be an emulsion, and isinterchangeably referred to as “emulsions.” The beads could be 10-100 μmin diameter, and have shell made of a material is stimuli-responsivepolymer, preferably a stimuli-responsive biodegradable polymer, such asthose disclosed in U.S. Patent Publication 20060127925, entitled“Stimuli-responsive polymer conjugates and related methods,” U.S. PatentPublication 20160263221, entitled “MULTI-RESPONSIVE TARGETING DRUGDELIVERY SYSTEMS FOR CONTROLLED-RELEASE PHARMACEUTICAL FORMULATION,”U.S. Patent Publication 20170119785, entitled “SOL-GEL POLYMERCOMPOSITES AND USES THEREOF,” U.S. Patent Publication 20170165201,entitled “PH-RESPONSIVE MUCOADHESIVE POLYMERIC ENCAPSULATEDMICROORGANISMS,” U.S. Patent Publication 20170135953, entitled “METHODSFOR LOCALIZED DRUG DELIVERY,” U.S. Patent Publication 20170073311,entitled “SUPRAMETALLOGELS AND USES THEREOF,” and U.S. PatentPublication 20170065721, entitled “SYNTHESIS AND USE OF THERAPEUTICMETAL ION CONTAINING POLYMERIC PARTICLES” which are incorporated, inrelevant parts for the purposes of written description, herein byreference in its entirety. The stimuli-responsive polymer could be atemperature-sensitive polymer, a pH-sensitive polymer, an electrical ormagnetic field-sensitive polymer, or a light-sensitive polymer. Anexample of a stimuli-responsive polymer is poly(N-isopropylacrylamide).A pH-sensitive polymer could dissociate or dissolve at the blood pH ofbetween 7.35 and 7.45. For example, the shell could be made of a polymerheld together by a polymer cross linker. The polymer could be apH-sensitive or a temperature-sensitive polymer that dissociates ordissolves at the blood pH of about 7.4 or the normal human bodytemperature of 36.5-37.5° C. (97.7-99.5° F.). Thus, the pH of thischamber within the implantable device would be lower than that of blood(below, 6.5, preferably below 5, e.g., between 1-3) or higher than thatof blood (above 8, preferably above 10, e.g., between 11-14), preventingany of the drug molecules from exiting through the beads in the acidicor basic flowable mixture (e.g., emulsion) within the implant. Once thebeads reach the blood stream, however, the drug would begin coming outof the beads as the beads dissociate or dissolve in blood. The shell ofthe bead could also contain an antibody for tumor targeting in the caseof cancer as well as gold particles to enhance radiation therapy. Theseare discussed in more detail in a later section.

As the piston gets pushed to the right, some of the bead-containingemulsion in the second middle chamber flows to the final chamber (VI).This third chamber would contain a foam, e.g., a biodegradable foam,that works as the flow control mechanism. The emulsions would passthrough the porous foam before reaching the 100-500 μm openingsbordering the circumference of chamber VI. These openings release thebead-containing emulsion from the implantable device to the bloodstream. The foam would act to prevent blood from entering the device andback-filling it. In addition to just acting as an obstruction betweenthe device and the blood, the foam can act to control the flow rate ofthe emulsions from the device to the body. More specifically, the foamwill have the property that it can be made more porous when sonicated.Thus, when the flow rate of the drug into the blood stream is smallerthan desired, sonication can be used to create more porosity in thefoam. Another way of creating greater porosity through the foam would bethrough a controlled explosion within the foam. Thereby, as the foamdisintegrates, it is easier for the emulsions to traverse from themiddle chamber out into the body.

The open cell biodegradable foam could be reticulated foam formed afterthermal reticulation such those disclosed in U.S. Pat. No. 8,801,801,entitled “AT LEAST PARTIALLY RESORBABLE RETICULATED ELASTOMERIC MATRIXELEMENTS AND METHODS OF MAKING SAME,” which is incorporated herein, inrelevant parts for the purposes of written description, in its entirety.In the biodegradable reticulated foam, the boundary skin layer formedduring the foaming process was trimmed and removed prior to subjectingthe as-made foam to thermal reticulation. The open cell biodegradablefoam in the embodiments herein is generally resilient to crushing whenimplanted within the body of a human or animal; thereby the open cellbiodegradable foam substantially maintains its original shape beforeimplantation even after implantation within the body of the human oranimal.

It is preferable to be able to control the flow rate of drug release tohave a multi-functional implant. More specifically—assuming that we wanta constant output of the pharmaceutical product—as liquids from the bodyenter the first chamber on the left due to osmosis, the pressure on thepiston will diminish over time. Thus, the rate at which drug exits theimplantable device will also decrease over time. To solve this problem,the implantable device will have a sensor on or in the rightmost sidewall (VII), e.g., an impermeable plug, and the sensor will measure theconcentration of drug in the blood at that spot. When the concentrationis below the desired threshold, the sensor will indicate to theon-implant sonicator (V) to turn on for a set number of seconds. Thissonicator is the barrier between the second and third chambers or withinthe third chamber as shown in FIG. 1, and as it sonicates, the foam willdegrade, making easier access for the drug-containing emulsions to reachthe openings bordering the blood stream. In this manner, the drug isreleased with a substantially constant concentration if theconcentration of the drug is within limits of Cmax and Cmin as shown inFIG. 3.

The limits of Cmin and Cmax are 80% to 125% of a desired concentration(which would be between the limits of Cmin and Cmax in FIG. 3) of thedrug in the body of the human or animal. These limits of Cmin and Cmaxare selected in the context of this invention because the United StatesFDA considers two products bioequivalent if the 90% confidence intervalof the peak concentration of a drug in the blood serum of a test sample(e.g. generic formulation) to reference (e.g. innovator brandformulation) is within 80% to 125% of a desired concentration of a drugin the blood serum.

The desired concentration could be substantially constant with time. Thedesired concentration could be substantially constant for a first periodof time and substantially zero for a second period of time, orvice-versa, or any combinations thereof. The desired concentration couldbe increasing or decreasing with time, or any combinations thereof.

In addition to dissolving or degrading the foam to increase the porosityof the foam and thereby increase the flow rate of the device, it may benecessary to lessen or even completely stop the drug release in certaincircumstances. This can be done by applying an external magnet, such asan electromagnet, atop the implantable device to prevent the piston,which could be made of magnetic material, from moving despite osmoticpressure. The strength of the magnetic force would be greater than thatof the fluid pressure, thereby stalling the piston. Since theimplantable device will be inserted either in the arm or near thestomach, such a magnet could be applied on an armband or beltsurrounding the device. Such a capability would allow a patient totemporarily stop drug release completely. Also, in case it is difficultto sonicate the biodegradable foam internally, a sonicator can beapplied externally on such an armband or belt. In this case, thebiosensor for drug concentration could send a signal to the patient(perhaps a text message to a phone or an email to a computer) indicatingthat the patient must apply the sonicator.

Further, instead of or in addition to having a foam for controlledrelease of the emulsions, the implantable device could encompass a platein lieu of or in addition to the sonicator (both are shown with numeralV in FIG. 1), as shown in FIG. 4, containing holes, some or all of whichthat are filled with phase-change material (PCM). Similar to thephysical (sonification) dependence of the state of the foam and thechemical (pH) dependence of the state of the emulsions, the PCM istemperature-dependent. Thus, when the sensor indicates that there is notenough drug in the blood stream, the patient could add heat to theimplantable device via the external belt or armband in order to melt thePCM and unclog the holes. As these holes are opened up, thebead-containing emulsion from the middle chamber will be flow moreeasily into the third chamber and eventually leave the device. Hence,this would be an alternative rate control mechanism.

In another embodiment, the first chamber containing the salt solutionand the second chamber containing the bead-containing emulsion can berecharged, for example, using a syringe containing the salt solution orthe bead-containing emulsion, even when the implantable device isimplanted in the body of the human or animal without removing theimplantable device from the body. This could be done through one or morehermetically-sealed valves in the casing, with the valves located inpositions above the first and second chambers. The hermetically-sealedvalve could be a pneumatically sealed valve or a slit valve such asthose disclosed U.S. Patent Publication 20140142556, entitled“IMPLANTABLE DRUG DELIVERY DEVICES” which is incorporated, in relevantparts for the purposes of written description, herein by reference inits entirety.

One way to refresh and/or increase the osmotic pressure of the saltsolution in the first chamber after implantation of the implantabledevice in the body would be to extract the used salt solution from thefirst chamber and replace it with a fresh salt solution. Similarly, oneway to refresh and/or increase the concentration of the drug in thesecond chamber after implantation of the implantable device in the bodywould be to extract the used emulsion containing the drug-containingbeads from the second chamber and replace it with a fresh emulsioncontaining the drug-containing beads or add a fresh emulsion containingthe drug-containing beads without removing the existing emulsion fromthe second chamber.

In another embodiment, the emulsion containing the drug-containing beadscould contain multiple drugs (a cocktail of drugs). In this case,different drugs could be encapsulated in different types of beads, withthe different types of beads having certain affinity for binding todifferent organs or tissues of the body, such as though differentfunctional groups attached to the different types of beads.

FIG. 5 shows a foam plug with a plate of FIG. 4 located within the plug.The plate could also function as an electrode (electrode 1) with acounter electrode (electrode 2) located at around one end of the foamplug. The combination of electrodes 1 and 2 could be used for creatingholes in the plate of FIG. 4 or to enhance or slow down the flow rate byelectrophoresis, which causes the motion of dispersed particles relativeto a fluid under the influence of a spatially uniform electric field.

Also, instead of applying external heat, the implantable device couldinternally contain electrodes that heat the PCM plate and dissolve someof the clogged holes. Different-sized holes could be plugged with PCMsof different melting points to ensure greater flexibility in controllingflow rate. MicroCHIPS technology, which was originally created in the1990s by MIT researchers Robert Langer and Michael Cima and PhD studentJohn Santini, and later licensed it out to MicroCHIPS. A diagram showinghow MicroCHIPS' wireless implantable device works is shown in FIG. 6(prior art). The following are the US patents of Langer and Cima, andthese US patents are incorporated herein, in relevant parts for thepurposes of written description, in their entirety by reference.

8,403,907 Full-Text Method for wirelessly monitoring implanted medicaldevice.

8,308,707 Full-Text Method and system for drug delivery to the eye.

7,918,842 Full-Text Medical device with controlled reservoir opening.

7,901,397 Full-Text Method for operating microchip reservoir device.

7,892,221 Full-Text Method of controlled drug delivery from implantabledevice.

7,879,019 Full-Text Method of opening reservoir of containment device.

7,776,024 Full-Text Method of actuating implanted medical device.

7,354,597 Full-Text Microscale lyophilization and drying methods for thestabilization of molecules.

7,226,442 Full-Text Microchip reservoir devices using wirelesstransmission of power and data.

7,070,592 Full-Text Medical device with array of electrode-containingreservoirs

7,070,590 Full-Text Microchip implants

6,976,982 Full-Text Flexible microchip devices for ophthalmic and otherapplications

6,808,522 Full-Text Microchip devices for delivery of molecules andmethods of fabrication thereof.

6,537,256 Full-Text Microfabricated devices for the delivery ofmolecules into a carrier fluid

6,491,666 Full-Text Microfabricated devices for the delivery ofmolecules into a carrier fluid

6,123,861 Full-Text Fabrication of microchip implants

5,797,898 Full-Text Microchip implants

5,514,378 Full-Text Biocompatible polymer membranes and methods ofpreparation of three dimensional membrane structures

Similar technology as that disclosed in the patents of Langer and Cimacan also be employed to generate controlled explosions of PCMs bygenerating electrical current and burning or melting the PCM membranesealing the holes, thereby unplugging the holes. The explosions in theplate with PCM in holes can be done similar to that in the MicroCHIPSimplant, for example, as and when required using a controllerappropriately spaced apart electrodes, either directly and automaticallybased on feedback from the sensor or externally by a person using aremote control device. Also, the explosions can be programmed ahead oftime into the implantable device when there is a reliably tested dosagecycle and the patient does not want make adjustments real-time.

Furthermore, some of the openings bordering the circumference of chamberVI can also be filled with phase-change material (PCM). These openingscould be explosively opened as explained above in the context of openingthe holes in the plate V of FIG. 4 wherein the holes that are filledwith phase-change material (PCM).

Besides the sensor being attached to the implant, there could be asecondary sensor inserted elsewhere in the body, preferably near atarget site. The secondary sensor could be a biodegradable sensor, forexample, such as that developed by a team from University of Illinois inUrbana and Washington University in St. Louis and published in the Jan.18, 2016, issue in the journal Nature, and subsequently disclosed onJan. 26, 2017, in U.S. Patent Publication 20170020402, entitled“IMPLANTABLE AND BIORESORBABLE SENSORS,” which is incorporated herein,in relevant parts for the purposes of written description, in itsentirety by reference.

Furthermore, the micro or nano beads could be of two or more types—thosethat rapidly break-up as soon as they leave the implantable device andthose that break-up after a longer period (several days) after exitingthe implantable device and travelling to the target site. The shell ofthe rapidly disintegrating beads could contain starch or cellulose.

In one embodiment, it is not necessary to include the first chamber andhave an osmosis-driven piston. Instead, the piston could be driven byelectro-magnetically using electromagnets in a device external to thebody in which the implantable device is implanted. In this case, theexternal device could be manufactured with circuitry that controls themovement of the piston. This system would allow extremely precise flowrates for the emulsions based on feedback from the sensor attached tothe implantable device or the secondary sensor inserted elsewhere in thebody, preferably near a target site. The sensors could send signalsindicating when to push, pull, or stop the piston entirely to allow forpre-programmed drug release for the patient.

The implantable device of the embodiments herein may require an energysource that is biocompatible and produces electricity. The energy sourcecould be as a battery, photo-energy source, or a galvanic cell. Thebatteries in the implantable device of the embodiments could be chargedexternally by radio-frequency (RF) charging.

In terms of target specificity for the beads, especially in the case ofcancer, it is important to lead the drug-encapsulated beads to the tumorsite. Thus, each bead will contain an antibody, corresponding toantigens on the site of the tumor, on its surface. The antibody would bejoined by a linker to the shell of the bead, and ensure that the drug isattracted toward the tumor as opposed to just free-floating in theblood. If the site of the tumor is known in advance, an additionalsensor could also be placed there to measure drug concentration. Thissensor can communicate with the sensor on the implantable device andthereby request for greater drug release in case the tumor is not beingproperly attacked. This interplay between sensors would greatly definethe conditions for controlled drug release. In addition, these beadscould have gold or platinum (or any other inert metal) attached to thesurface of the beads, e.g., composite inorganic organic nanoclusters(COINs), to tremendously help patients undergoing radiotherapy. Forexample, U.S. Patent Publication 20160129111, entitled “METHODS FORDELIVERING AN ANTI-CANCER AGENT TO A TUMOR,” which is incorporatedherein, in relevant parts for the purposes of written description,herein by reference in its entiretu, discloses methods for delivering ananti-cancer agent to a tumor in a subject. The method involvesadministering to the subject (i) gold particles and (ii) at leastone-anti-cancer agent directly or indirectly bonded to the macromoleculeand/or unbound to the macromolecule; and exposing the tumor to light fora sufficient time and wavelength in order for the gold particles toachieve surface plasmon resonance and heating the tumor.

COINs are composed of a metal, preferably an inert metal such as gold orplatinum, and at least one organic radiation-active compound. Forexample, Raman-active COINS are disclosed in U.S. Pat. No. 7,790,286,which is incorporated herein, in relevant parts for the purposes ofwritten description, in its entirety by reference. Interactions betweenthe metal of the clusters and the radiation-active compound(s) enhancethe radiation signal obtained from a radiation-active compound when thenanoparticle is excited. Since a large variety of organicradiation-active compounds can be incorporated into the nanoclusters, aset of COINs can be created in which each member of the set has aradiation enhancement unique to the set. Also, COINs can also functionas sensitive reporters for highly parallel detection of the beads.Furthermore, treatment specificity can be enhanced by incorporatingthousands of gold or platinum particles into a single nanocluster and/orattaching multiple nanoclusters to a single bead.

More specifically, once the beads are attached to the tumor site, thegold or platinum particles amplify the radiation that is presented atthe tumor site, preventing the need for exorbitantly high levels ofradiation that can oftentimes be dangerous to the individual. Thus,through the combination of a target antibody, a sensor at the tumorsite, and gold/platinum particle technology, the implantable devicewould address the issue of treatment specificity, which is incrediblyproblematic in oncology care.

In one embodiment, the nano or micro beads could comprise a shellcomprising a first material and a second material, wherein the secondmaterial comprises a biodegradable material; a core comprising apharmaceutically effective composition, the core being enclosed by theshell; wherein the first material is distributed in the biodegradablematerial; wherein the first material is configured to create holes inthe shell; wherein the holes allow the pharmaceutically effectivecomposition to be released to the exterior of the shell through theholes. In one embodiment, the shell could be made by polymerizing asilica-functionalized monomer to form a silica-containing biodegradablepolymer shell.

In the implant, the pharmaceutically effective composition couldcomprise a targeting material or molecule that binds to a certain organ,object or a specific site within a body of a human or an animal. Thus,for example, even if the drug is the same but used for differentcancers, then using a targeting molecule for a particular type ofcancer, e.g., breast cancer, then the drug would bind to the cells ofthat particular type of cancer. On the other hand, if the drug isintended for ovarian cancer, then the target molecule could bespecifically one that binds to the cells of ovarian cancer. Thetargeting material or molecule could be a biomarker.

An ingredient of the pharmaceutically effective composition could be amaterial that prevents the pharmaceutically effective composition frombeing taken up by the host defense as white blood and macrophages in thehuman or animal body. Such an ingredient remains in the blood but thebody organs cannot take it up. An example of such an ingredient ispolyethylene glycol (PEG), e.g., having 200 Dalton molecular weight.

In another embodiment, the biodegradable shell of the nano or microbeads could contain a controlled release ingredient that functions as acontrol release sensor to control the release of the drug. For example,one would want a particular concentration of the drug at a given siteover a given extended period of time. The control release ingredientcould be a material that degrades faster than the remaining material ofthe biodegradable shell of the nano or micro beads or punches holes(pores) in biodegradable shell of the nano or micro beads.

The holes in the biodegradable shell of the nano or micro beads could bepunched by giving external stimuli such as sound, such as ultrasonicsound, radio frequency heating, radiation or microwave to the drugcontaining beads. The external stimulus heats up the controlled releaseingredient, thereby punching one or more holes in the shell surroundingthe controlled release ingredient, which could be a metal-containingmaterial is configured to form holes in the shell, before or afterimplanting or attaching the device in or on a body of a human or ananimal, when the shell is exposed to an external stimulus. For example,the controlled release ingredient that can be used for punching holes inthe shell could be molecular iron such a magnetic resonance imaging(MRI) contrast agent. Depending on the concentration of the controlledrelease ingredient, one can control the number of holes punched in theshell, which in turn controls the amount of drug released from the coreto the outside of the shell.

Two types of iron oxide MRI contrast agents exist: superparamagneticiron oxide (SPIO) and ultrasmall superparamagnetic iron oxide (USPIO).These contrast agents consist of suspended colloids of iron oxidenanoparticles. A FDA approved iron oxide MRI contrast is Lumirem (alsoknown as Gastromark).

Other controlled release ingredients for punching holes in the shellcould be superparamagnetic iron platinum particles (SIPPs). SIPPs couldalso encapsulated with phospholipids to create multifunctional SIPPstealth immunomicelles that specifically targeted human prostate cancercells.

Yet, other controlled release ingredients for punching holes in theshell are Mn-based nanoparticles. Manganese ions (Mn2+) are often usedas a contrast agent in animal studies, usually referred to as MEMRI(Manganese Enhanced MRI). For example, Mn2+ carbon nanostructurecomplexes of graphene oxide nanoplatelets and graphene oxide nanoribbonscould also be used as controlled release ingredients.

In addition to or in lieu of the osmotic pump option of pumping theemulsion from the pump chamber containing the emulsion could be by usingshape memory alloy (e.g., nitinol) spring that is connected to thepiston and attached to a hook inside the implantable device opposite thepiston. For example, the hook could be attached to the plate V shown inFIG. 4 and discussed above, or the front end of the implantable deviceattached to the wall on the right side of the third chamber (IV) inFIG. 1. The shape memory alloy spring could be heated using externalheating, e.g., radio frequency heating.

The advantages of the present invention will become readily apparent bythose skilled in the art from the following detailed description,wherein it is shown and described preferred embodiments of theinvention, simply by way of illustration of the best mode contemplatedof carrying out the invention. As will be realized the invention iscapable of other and different embodiments, and its several details arecapable of modifications in various obvious respects, without departingfrom the invention. Accordingly, the description is to be regarded asillustrative in nature and not as restrictive.

Uses Thereof:

Use of such device for systemic delivery any active pharmaceuticalingredient in humans or animals, as a patient convenience to avoiddaily, weekly or monthly oral, subcutaneous or intravenousadministration.

Use of such device for systemic delivery any biologic therapy in humansor animals as a means of patient convenience to overcome daily, weeklyor monthly oral, subcutaneous or monthly administration. Biologicmolecules can be peptides, antibodies or fragments thereof, nucleic acidmolecules such as modified RNA, small interfering RNA, anti-sense DNAmolecules or fragments thereof.

Use of such device to deliver antigens to elicit vaccine responses inhumans or animals.

Use of such device to provide local tissue delivery of any therapeuticmolecule, be it small molecule or biologic.

Use of such device to provide long-term sustained release of insulin oranalogs thereof, alone or in combination of other therapies, to treatdiabetes or other metabolic conditions.

Use of such device to provide long-term sustained release of GLP-1 oranalogs thereof, alone or in combination of other therapies, to treatdiabetes or other metabolic conditions.

Deposition of such device underneath the skin, or in fat tissue or inany specific organ for the purpose of long-term release of anytherapeutic molecule, be it either a small molecule or biologic.

Specific use of such device to provide sustained long-term release ofcontraceptive hormones, combination of estrogen or progestin or singulardelivery of progesterone alone and serve as contraceptive aid for women.

Specific use of such device for the intraocular delivery of any smallmolecule or biologic therapy as a means to provide the long-termtherapeutic benefit for ocular diseases, such as age related maculardegeneration, dry eye and various others. Deposition of such device anduse to directly into bladder for long-term delivery of any smallmolecule or biologic therapy to treat urinary bladder complications suchas incontinence, yeast infections, bladder cancer and various others.

Deposition of such device and use to locally deliver therapeuticmolecules to the male reproductive organs as a means to treat medicalconditions such as erectile dysfunction, premature ejaculation,testicular cancer and various others pertaining to male reproductivesystem.

Deposition of such device and use to locally deliver therapeuticmolecules to female reproductive organs, uterus and ovaries, to treatmedical conditions such as endometriosis, uterine fibroids, ovariancancer, uterine cancer, poly cystic ovarian syndrome, and various otherdisease pertaining to female reproductive system.

Deposition of such device and use to locally deliver therapeuticmolecules to heart conditions such as heart failure, myocardialischemia, and various other heart diseases.

Deposition of such device and use to locally deliver therapeuticmolecules into the adipose tissue to treat conditions such as metabolicsyndrome, diabetes, hypercholesterolemia, hypertriglyceridemia andvarious others.

In embodiments herein, depending on the dosing requirements of aparticular drug, the device can provide a constant drug concentration oreven an increasing drug concentration or a decreasing drug concentrationover time. The device can also provide a constant concentration for acertain amount of time, followed by no drug release for some time, andsubsequently followed by the same concentration from the beginning. Thiswould be especially useful in the case of birth control medication; fora short period of time when a woman wants to get pregnant, theimplantable device can stop the release of the drug, and then continueit again afterwards. Thus, embodiments herein relate to a highlycontrolled delivery system by which any permutation of drug releaseprofiles could be either programmed ahead of time or even implemented inreal-time.

What is claimed is:
 1. A system comprising an implantable device and anenergy source that produces electricity, the implantable devicecomprising: A. a casing that is substantially tubular and has at least afirst end and a second end opposite to the first end, B. a firstchamber, C. a second chamber comprising a drug, D. a third chamber, E. asemi-permeable membrane plug at or near the first end, F. a piston, G. aplate with holes therein, and H. an opening for release of the drug fromthe implantable device into a body of a human or an animal; wherein: a.the implantable device is configured to be implanted within the body ofthe human or the animal during delivery of the drug into the body of thehuman or the animal, b. the piston is located between the semi-permeablemembrane plug and the plate, c. the plate is located between the pistonand the second end, d. the first chamber occupies volume between thesemi-permeable membrane plug and the piston, e. the second chamberoccupies volume between the piston and the plate, f. the third chamberoccupies volume between the second chamber and the second end; and g.the implantable device is configured to produce a desired flow rate ofelution of the drug from the implantable device by delivering aconsistent drug level through the opening.
 2. The system of claim 1,wherein delivery of the consistent drug level by the implantable devicecomprises a desired dosage cycle.
 3. The system of claim 1, whereindepending on a dosing requirement of a particular drug, the implantabledevice provides over time a constant drug concentration, an increasingdrug concentration or a decreasing drug concentration.
 4. The system ofclaim 1, wherein the implantable device provides a constantconcentration for a certain amount of time, no drug release for sometime, and repeats the constant concentration for the certain amount oftime.
 5. The system of claim 1, wherein the system delivers theconsistent drug level by producing a drug release profile that is eitherprogrammed ahead of time or implemented in real-time.
 6. The system ofclaim 1, wherein the desired flow rate of elution the drug is such thata maximum limit and a minimum limit of a concentration of the drug in ablood serum of the human or the animal are Cmax and Cmin, respectively.7. The system of claim 6, wherein the Cmin and the Cmax are 80% to 125%of a desired concentration of the drug in the body of the human or theanimal.
 8. The system of claim 6, wherein the Cmin and the Cmax are suchthat a 90% confidence interval of a peak concentration of the drug inthe blood serum of the human or an animal versus a reference is within80% to 125% of a desired concentration of the reference in the bloodserum of the human or the animal, wherein the reference is a productapproved by United States Food and Drug Administration.
 9. The system ofclaim 1, wherein the energy source is biocompatible.
 10. The system ofclaim 1, wherein the implantable device comprises the energy source. 11.The system of claim 1, wherein the energy source comprises a battery, aphoto-energy source, or a galvanic cell.
 12. The system of claim 11,wherein the battery is charged by radio-frequency (RF) charging.
 13. Thesystem of claim 1, further comprising an electromagnet and a circuitry.14. The system of claim 1, further comprising a sensor attached to theimplantable device.
 15. The system of claim 1, further comprising asensor that is placed within the body of the human or the animal tomeasure a drug concentration.
 16. A system comprising (A) a remotecontrol device, (B) an energy source that produces electricity, and (C)an implantable device comprising (i) an osmotic pump comprising apiston, (ii) a drug, and (iii) a plate with holes therein; wherein: a.the implantable device is configured to be implanted within a body of ahuman or an animal during delivery of the drug into the body of thehuman or the animal, and b. the implantable device delivers a consistentdrug level through an opening.
 17. The system of claim 16, whereindelivery of the consistent drug level by the implantable devicecomprises a dosage cycle.
 18. The system of claim 16, wherein dependingon a dosing requirement of a particular drug, the implantable deviceprovides over time a constant drug concentration, an increasing drugconcentration or a decreasing drug concentration.
 19. The system ofclaim 16, wherein the implantable device provides a constantconcentration for a certain amount of time, no drug release for sometime, and repeats the constant concentration for the certain amount oftime.
 20. A method of treating a disease comprising delivering a drug ina body of a human or an animal using a system comprising (A) a remotecontrol device, (B) an energy source that produces electricity, and (C)an implantable device comprising (i) an osmotic pump comprising apiston, (ii) a drug, and (iii) a plate with holes therein; wherein: a.the implantable device is configured to be implanted within the body ofthe human or the animal during delivery of the drug into a body of ahuman or an animal, and b. the implantable device delivers a consistentdrug level through an opening.